1. Field of the Invention
This invention relates broadly to the controlled release of drugs to the bloodstream and tissues of mammals and more particularly to a shaped article formed from a biodegradable polymer which contains one or more anticancer agents so that the article is suitable for implantation in a mammal to controllably release the anticancer agents.
2. Description of the Prior Art
Medical science has long recognized the need for methods to controllably release therapeutic agents and other drugs to the bodies of patients. Recently, a great deal of research has been initiated in attempting to find new release systems to fulfill this need. Several such systems have been recommended.
One common method for obtaining controlled release is to envelop the active substance with coatings which are attacked by digestive juices in the stomach. This technique has been widely used recently for time-release analgesics. There are some problems with this method, however, such as: (1) it is difficult to obtain the proper distribution of coating thicknesses to give the desired release; and (2) the sojourn time of the coated agent in the digestive tract is relatively short, thereby making this unsuitable for long-term release.
Another method of obtaining controlled release is to mix the active substance with various binders such as fats, waxes, and natural or synthetic polymers to slow down release. Many of the binders, however, are unsuitable for use with many drugs. Furthermore, these combinations of binders and drugs tend to disperse quickly after they enter the body due to the binder's solubility in body fluids, the washing effect of the body fluids and/or the attack of digestive juices. After the binder has been so dispersed, all control over the release of the drug is lost.
Other researchers have even suggested that drugs be chemically modified to affect their release and absorption into the bloodstream. The degree of difficulty of this method for obtaining controlled release is clear.
More recently, the possibility of somehow incorporating drugs into polymeric materials to control drug release has been considered. Thus Furuse et al., U.S. Pat. No. 3,514,517, teach that suppositories containing spermicidal agents can be formed by blending the agents with low molecular weight polyethylene glycols; Hill, U.S. Pat. No. 3,458,622, teaches that tablets for controlling the release of medicinal agents for up to eight hours can be formed from a blend of a polymeric vinyl pyrrolidone with a carboxy vinyl hydrophilic polymer; Weil et al., U.S. Pat. No. 3,469,005, teach that drugs for reducing blood pressure in mammals can be incorporated into solid vehicles such as lactose, cornstarch, microcrystalline cellulose, talc, stearic acid, magnesium stearate, gums, etc.; Merabi et al., U.S. Pat. No. 3,495,000, have found that controlled release matrices can be prepared consisting of a dialdehyde starch and ethyl cellulose, polyvinyl chloride or polyvinylpyrrolidone, but that mixtures of the same starches with other pharmaceutically acceptable polymers such as methylcellulose or carboxymethylcellulose do not yield compositions suitable for controlled release; and Herrmann, U.S. Pat. No. 2,155,658, teaches that medical preparations for injection into the body which are flowable above body temperature but solid at body temperature after injection ca be made from polymerized vinyl alcohols and their water soluble derivatives and a solvent for such material.
Another technique for incorporating drugs into polymeric matrices is described in Levesque, U.S. Pat. No. 2,987,445 and in Edicott, U.S. Pat. No. 3,087,860. These patents teach a drug dispenser formed from synthetic polymers containing solid particles of a water-leachable drug. Usually the polymer matrix is shaped in the form of a pill which is intended to be orally ingested. This drug dispenser is limited, however, to water-soluble drugs and has relatively short release times, i.e., typically 8-12 hours.
While the above-mentioned patents describe various mixtures of drugs with polymers, Long et al. have taught another method for constructing a controlled release device from polymers in U.S. Pat. No. 3,279,996. Long et al. form a capsule or container from polysiloxane which is intended for implantation. This device has the advantage of making extended time-release treatment possible, but suffers a disadvantage since the possibility exists that the polysiloxane container will develop pinholes or a rupture resulting in an undesired and potentially harmful large amount of drug being released almost instantaneously.
A polymeric drug dispenser formed from crystalline polymeric materials is disclosed in U.S. Pat. No. 3,880,991, issued on Apr. 29, 1975. The device described therein offers many improvements over existing controlled release devices, but suffers a disadvantage when subcutaneously implanted since the polymers described therein are not biodegradable. Thus, a separate removal step often necessitating minor surgery is required.
Biodegradable polymer matrices have been previously described in my earlier applications, including Ser. Nos. 504,588, filed Dec. 9, 1974; 102,431, filed Dec. 29, 1970; and 809,946, filed Mar. 24, 1969. Additionally, poly(lactic acid) has been disclosed by others for this use in U.S. Pat. No. 3,773,919 issued Dec. 20, 1973. Poly(lactic acid) films have also been shown to release anticancer agents such as cyclophosphamide and cis-dichlorodiammine-platinum(II) in healthy rats. See Yolles, S., Leafe, T. D., and Meyer, F. J., "Timed-Release Depot for Anticancer Agents," J. Pharm. Sci., 64, No. 1, pp. 115-6, Jan. 1975.